The present invention relates to methods for treating inflammatory disorders. More specifically, the present invention concerns the control of the generation of free radicals in the immune response.
Phagocytic leukocytes are an important part of the body's defense against invasions of pathogenic microbes and cleansing mechanisms for dead and dying cells. Phagocytic leukocyte is a term that encompasses neutrophils, eosinophils, and macrophages. These phagocytic cells are most often brought to the source of invasion by the bloodstream. Certain macrophages also reside in the tissues of various organs. Once these phagocytic cells are brought in contact with microbes or cellular debris they engulf, or "phagocytize", the material. The destruction of the engulfed material is brought about by the reaction of such material with highly reactive chemical species generated by membrane-bound enzymes in the phagocytic cell. In particular, the enzyme NADPH oxidase catalyzes the consumption of oxygen by producing a superoxide anion (O.sub.2.sup.-) according to the following formula: EQU NADPH+H.sup.+ +20.sub.2 .fwdarw.NADP.sup.+ +2H.sup.+ +20.sub.2 -
The superoxide anion is able to pass through cell membranes through anion channels to the enveloped biological material. While the superoxide anion may have some direct toxic effects on the engulfed material, it also exerts its toxicity through its conversion to other toxic products known collectively as reactive oxygen species (ROS). Such conversions are happening both chemically and enzymatically within the phagocyte.
Unfortunately, during the process of phagocytosis, these ROS escape from the phagocytic cells into the surrounding cytosol, contacting normal cells in healthy tissue. Such cells and tissues have developed an extensive array of protective enzymic and non-enzymic antioxidants that will decompose these potentially injurious oxidizing agents. During the inflammatory response to these invading microbes, these defenses degrade most oxidants that escape phagocytic cells, thereby limiting the injury to the surrounding tissue until the inflammatory response subsides. However, sustained production of ROS as during chronic inflammation can overwhelm these cellular defenses and damage the healthy tissue. The overproduction of ROS is implicated in the pathogenesis of many diseases, e.g., respiratory distress syndromes, rheumatoid arthritis, ischemia-reperfusion injury and inflammatory bowel disease.
Thus, modulating the production and toxicity of ROS by neutrophils and macrophages would offer one approach to treating inflammatory diseases such as inflammatory bowel disease. In recent years, three strategies have evolved based on this approach. One such effort has focused on the removal of oxygen radicals with scavenger enzymes such as superoxide dismutase, catalase or similar preparations. Unfortunately, a complicating factor arising in the treatment of chronic inflammatory diseases with these agents is establishing a continuous systemic supply of the scavenger enzymes, as these are rapidly degraded and removed from the body by mechanisms such as digestion by peptidases and the like. Attempts have also been made to identify non-protein mimics of superoxide dismutase but to date such efforts have been unsuccessful.
A second approach had been the prevention of iron-dependent ROS formation by chelation of iron with compounds such as desferrioxamine. A third approach has been to prevent the generation of radicals by NADPH oxidase through the use of compounds such as diphenylene iodonium. Unfortunately, various side effects (including lack of specificity for enzyme inhibitors) complicate the clinical application of the drugs used in these latter two approaches for the treatment of inflammatory diseases.
Thus, it would be advantageous to discover methods which modulate or otherwise ameliorate the oxidative burst pathway of phagocytes and other types of immune cells for use in treatments for inflammatory diseases such as inflammatory bowel disorder.